Abstract
Introduction: Histone Deacetylase 6 (HDAC6) has been exploited as a target for drug design due to its role in cancer. Targeting HDAC6 as a monotherapy or in combination with other drugs results in apoptosis of many cancer cell types. The crystal structure of HDAC6 was published in 2016 and provided an opportunity to conduct molecular dynamic (MD) simulations of this protein. Low HDAC6 expression is significantly associated with poor overall survival in HGSOC and understanding the molecular interactions of HDAC6 in HGSOC cells may uncover additional treatment options for this disease.
Methods: Protein flexibility was measured using the Relative Mean Standard Fluctuation (RMSF). Correlation networks were created using Bio3D. Ligand-residue interaction energies were calculated using Schrodinger. FTMap and FTSite were used to predict potential exosites. In vitro analysis of HDAC6 molecular interactions and cellular responses to ACY-1215 were measured in HEK293 cells and in sv40 transformed human HGSOC cell lines.
Results: The results decipher allosteric correlated protein segments and loop dynamic motions. Analysis of ligand–residue interactions has identified key binding residues. Exosite mapping has predicted potential ‘druggable’ sites opening the possibility of inhibition outside of the active site. HDAC6 weakly associates with HSP90 irrespective of the presence of the catalytic HDAC6 domain. The selective inhibition of HDAC6 was associated with adverse cellular responses which lead to an increase in the clonogenicity of HGSOC. HDAC6 inhibition did not sensitise HGSOC cells to paclitaxel.
Conclusion: Inhibitor binding depends upon two important residues in the catalytic domains of HDAC6 (CD1: H139 and H140; CD2: H610 and H611). π- π stacking interactions exist. Exosites have been identified that could be exploited for future drug design. HDAC6 inhibition alone is not sufficient to kill HGSOC. Further interrogation of the molecular interactions of HDAC6 may provide a strategy for more effective targeting of HDAC6.
Methods: Protein flexibility was measured using the Relative Mean Standard Fluctuation (RMSF). Correlation networks were created using Bio3D. Ligand-residue interaction energies were calculated using Schrodinger. FTMap and FTSite were used to predict potential exosites. In vitro analysis of HDAC6 molecular interactions and cellular responses to ACY-1215 were measured in HEK293 cells and in sv40 transformed human HGSOC cell lines.
Results: The results decipher allosteric correlated protein segments and loop dynamic motions. Analysis of ligand–residue interactions has identified key binding residues. Exosite mapping has predicted potential ‘druggable’ sites opening the possibility of inhibition outside of the active site. HDAC6 weakly associates with HSP90 irrespective of the presence of the catalytic HDAC6 domain. The selective inhibition of HDAC6 was associated with adverse cellular responses which lead to an increase in the clonogenicity of HGSOC. HDAC6 inhibition did not sensitise HGSOC cells to paclitaxel.
Conclusion: Inhibitor binding depends upon two important residues in the catalytic domains of HDAC6 (CD1: H139 and H140; CD2: H610 and H611). π- π stacking interactions exist. Exosites have been identified that could be exploited for future drug design. HDAC6 inhibition alone is not sufficient to kill HGSOC. Further interrogation of the molecular interactions of HDAC6 may provide a strategy for more effective targeting of HDAC6.
| Original language | English |
|---|---|
| Publication status | In preparation - 2019 |
| Event | 55th Irish Association for Cancer Research Conference 2019 - Europa Hotel, Belfast, United Kingdom Duration: 20 Feb 2019 → 22 Feb 2019 https://www.iacr.ie/2019-annual-conference/ |
Conference
| Conference | 55th Irish Association for Cancer Research Conference 2019 |
|---|---|
| Abbreviated title | IACR 2019 |
| Country/Territory | United Kingdom |
| City | Belfast |
| Period | 20/02/2019 → 22/02/2019 |
| Internet address |
